Transcriptomic analysis of hepatic responses to testosterone deficiency in miniature pigs fed a high-cholesterol dietReport as inadecuate

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BMC Genomics

, 16:59

First Online: 06 February 2015Received: 21 October 2014Accepted: 26 January 2015DOI: 10.1186-s12864-015-1283-0

Cite this article as: Cai, Z., Jiang, X., Pan, Y. et al. BMC Genomics 2015 16: 59. doi:10.1186-s12864-015-1283-0


BackgroundRecent studies have indicated that low serum testosterone levels are associated with increased risk of developing hepatic steatosis; however, the mechanisms mediating this phenomenon have not been fully elucidated. To gain insight into the role of testosterone in modulating hepatic steatosis, we investigated the effects of testosterone on the development of hepatic steatosis in pigs fed a high-fat and high-cholesterol HFC diet and profiled hepatic gene expression by RNA-Seq in HFC-fed intact male pigs IM, castrated male pigs CM, and castrated male pigs with testosterone replacement CMT.

ResultsSerum testosterone levels were significantly decreased in CM pigs, and testosterone replacement attenuated castration-induced testosterone deficiency. CM pigs showed increased liver injury accompanied by increased hepatocellular steatosis, inflammation, and elevated serum alanine aminotransferase levels compared with IM pigs. Moreover, serum levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides were markedly increased in CM pigs. Testosterone replacement decreased serum and hepatic lipid levels and improved liver injury in CM pigs. Compared to IM and CMT pigs, CM pigs had lower serum levels of superoxide dismutase but higher levels of malondialdehyde. Gene expression analysis revealed that upregulated genes in the livers of CM pigs were mainly enriched for genes mediating immune and inflammatory responses, oxidative stress, and apoptosis. Surprisingly, the downregulated genes mainly included those that regulate metabolism-related processes, including fatty acid oxidation, steroid biosynthesis, cholesterol and bile acid metabolism, and glucose metabolism. KEGG analysis showed that metabolic pathways, fatty acid degradation, pyruvate metabolism, the tricarboxylic acid cycle, and the nuclear factor-kappaB signaling pathway were the major pathways altered in CM pigs.

ConclusionsThis study demonstrated that testosterone deficiency aggravated hypercholesterolemia and hepatic steatosis in pigs fed an HFC diet and that these effects could be reversed by testosterone replacement therapy. Impaired metabolic processes, enhanced immune and inflammatory responses, oxidative stress, and apoptosis may contribute to the increased hepatic steatosis induced by testosterone deficiency and an HFC diet. These results deepened our understanding of the molecular mechanisms of testosterone deficiency-induced hepatic steatosis and provided a foundation for future investigations.

KeywordsTestosterone Nonalcoholic fatty liver disease Hepatic steatosis Miniature pigs RNA-Seq AbbreviationsALTAlanine aminotransferase

ANOVAAnalysis of variance

ARAndrogen receptor

ASTAspartate aminotransferase


DEGDifferentially expressed gene

FDRFalse discovery rate

FFAFree fatty acid

GOGene ontology

GSH-PXGlutathione peroxidase

HandEHematoxylin and eosin

HDL-CHigh-density lipoprotein cholesterol

HFCHigh-fat and high-cholesterol

LDL-CLow-density lipoprotein cholesterol

NAFLDNonalcoholic fatty liver disease

NASHNonalcoholic steatohepatitis

PBSPhosphate-buffered saline


qRT-PCRQuantitative real-time reverse transcription polymerase chain reaction

RINRNA integrity number

RNA-SeqRNA sequencing

SEMStandard error of the mean

SODSuperoxide dismutase


TCTotal cholesterol

TfmTesticular feminized mice


STEMShort Time-Series Expression Miner

Electronic supplementary materialThe online version of this article doi:10.1186-s12864-015-1283-0 contains supplementary material, which is available to authorized users.

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Author: Zhaowei Cai - Xiaoling Jiang - Yongming Pan - Liang Chen - Lifan Zhang - Keyan Zhu - Yueqin Cai - Yun Ling - Fangming Che


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